scholarly journals Platelet-neutrophil aggregates promote skin pathology in psoriasis

2019 ◽  
Author(s):  
Franziska Herster ◽  
Zsofia Bittner ◽  
Marius Cosmin Cordrea ◽  
Nate Archer ◽  
Martin Heister ◽  
...  
Keyword(s):  
Disease Severity ◽  
Psoriasis Patient ◽  
Surface Antigens ◽  
Skin Lesions ◽  
Human Neutrophils ◽  
Psoriatic Skin ◽  
List Type ◽  
Platelet Surface ◽  
Cardiovascular Comorbidities

AbstractPsoriasis is a frequent systemic inflammatory autoimmune disease characterized primarily by skin lesions with massive infiltration of leukocytes but frequently also presents with cardiovascular comorbidities. Especially polymorphonuclear neutrophils (PMNs) abundantly infiltrate psoriatic skin but the cues that prompt PMNs to home to the skin are not well defined. To identify PMN surface receptors that may explain PMN skin homing in psoriasis patients, we screened 332 surface antigens on primary human blood PMNs from healthy donors and psoriasis patients. We identified platelet surface antigens as a defining feature of psoriasis PMNs, due to a significantly increased aggregation of neutrophils and platelets in the blood of psoriasis patients. Similarly, in the imiquimod-induced experimental in vivo model of psoriasis, disease induction promoted PMN-platelet aggregate formation. In psoriasis patients, disease directly correlated with blood platelet counts and platelets were detected in direct contact with PMNs in psoriatic but not healthy skin. Importantly, depletion of circulating platelets in vivo ameliorated disease severity significantly, indicating that the intimate relationship of PMNs and platelets may be relevant for psoriasis pathology and disease severity, and potentially for psoriasis-associated cardiovascular comorbidities.Key pointsHuman neutrophils in psoriasis patient blood show a distinct ‘platelet signature’ of surface antigensPlatelets congregate with neutrophils in psoriatic skin lesionsCirculating platelets contribute to psoriasis skin pathology

scholarly journals Self-RNA–antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8

2009 ◽  
Vol 206 (9) ◽  
pp. 1983-1994 ◽  
Author(s):  
Dipyaman Ganguly ◽  
Georgios Chamilos ◽  
Roberto Lande ◽  
Josh Gregorio ◽  
Stephan Meller ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Inflammatory Responses ◽  
Skin Lesions ◽  
Psoriatic Skin ◽  
Cationic Antimicrobial Peptide ◽  
Tnf Α ◽  
Peptide Complexes ◽  
Human Dendritic Cells ◽  
Dying Cells

Dendritic cell (DC) responses to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid–recognizing Toll-like receptors (TLRs). In psoriasis, however, plasmacytoid DCs (pDCs) sense self-DNA that is transported to endosomal TLR9 upon forming a complex with the antimicrobial peptide LL37. Whether LL37 also interacts with extracellular self-RNA and how this may contribute to DC activation in psoriasis is not known. Here, we report that LL37 can bind self-RNA released by dying cells, protect it from extracellular degradation, and transport it into endosomal compartments of DCs. In pDC, self-RNA–LL37 complexes activate TLR7 and, like self-DNA–LL37 complexes, trigger the secretion of IFN-α without inducing maturation or the production of IL-6 and TNF-α. In contrast to self-DNA–LL37 complexes, self-RNA–LL37 complexes also trigger the activation of classical myeloid DCs (mDCs). This occurs through TLR8 and leads to the production of TNF-α and IL-6, and the differentiation of mDCs into mature DCs. We also found that self-RNA–LL37 complexes are present in psoriatic skin lesions and are associated with mature mDCs in vivo. Our results demonstrate that the cationic antimicrobial peptide LL37 converts self-RNA into a trigger of TLR7 and TLR8 in human DCs, and provide new insights into the mechanism that drives the auto-inflammatory responses in psoriasis.

scholarly journals Rapamycin Alleviates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Aggravated Dermatitis in Mice with Imiquimod-Induced Psoriasis-Like Dermatitis by Inducing Autophagy

2021 ◽  
Vol 22 (8) ◽  
pp. 3968
Author(s):  
Hye Ran Kim ◽  
Jin Cheol Kim ◽  
Seok Young Kang ◽  
Hye One Kim ◽  
Chun Wook Park ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Skin Inflammation ◽  
Skin Lesions ◽  
Psoriatic Skin ◽  
Related Factor ◽  
Related Factors ◽  
Tetrachlorodibenzo P Dioxin

Recently, the mTOR signaling has emerged as an important player in the pathogenesis of psoriasis. We previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced psoriatic skin inflammation was related to the inhibition of autophagy in keratinocytes. However, the effects and detailed molecular mechanisms of the mTOR inhibitor rapamycin and TCDD on psoriasis in vivo remain to be elucidated. In this study, we aimed to evaluate the effects of rapamycin and TCDD on skin lesions in imiquimod (IMQ)-induced psoriasis using a mouse model. TCDD aggravated skin inflammation in an IMQ-induced psoriatic mouse model. Furthermore, TCDD increased the expression of aryl hydrocarbon receptor (AHR), CYP1A1, proinflammatory cytokines, oxidative stress markers (NADPH oxidase (Nox) 2, Nox4), and phosphorylated P65NF-ĸB, whereas the expression of autophagy-related factors and the antioxidant marker nuclear factor-erythroid 2-related factor 2 (NRF2) decreased. Rapamycin reduced the aggravated skin inflammation induced by TCDD and restored TCDD-induced autophagy suppression and the increase of AHR expression, oxidative stress, and inflammatory response in the skin lesions of a psoriatic mouse model. In conclusion, we demonstrated that rapamycin alleviates TCDD-induced aggravated dermatitis in mice with imiquimod-induced psoriasis-like dermatitis through AHR and autophagy modulation.

scholarly journals Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis

2018 ◽  
Vol 2018 ◽  
pp. 1-18 ◽  
Author(s):  
Martina Morelli ◽  
Claudia Scarponi ◽  
Laura Mercurio ◽  
Francesco Facchiano ◽  
Sabatino Pallotta ◽  
...  
Keyword(s):  
Skin Lesions ◽  
Janus Kinase ◽  
Psoriatic Skin ◽  
Epidermal Keratinocytes ◽  
Cytokine Signaling ◽  
Molecular Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Inflammatory Genes

IFN-γ and IL-22 are deeply involved in the pathogenesis of psoriasis, as they boost the expression of inflammatory genes and alter proliferative and differentiative programs in keratinocytes. The JAK1/JAK2/STAT1 and JAK1/TYK2/STAT3 pathways triggered by IFN-γ and IL-22, respectively, are aberrantly activated in psoriasis, as highlighted by the peculiar STAT1 and STAT3 signatures in psoriatic skin lesions. To limit the detrimental consequences of IFN-γ and IL-22 excessive stimulation, psoriatic keratinocytes activate suppressor of cytokine signaling (SOCS)1 and SOCS3, which in turn dampen molecular signaling by inhibiting JAK1 and JAK2. Thus, JAK targeting appears to be a reasonable strategy to treat psoriasis. Tofacitinib is an inhibitor of JAK proteins, which, similarly to SOCS, impedes JAK phosphorylation. In this study, we evaluated the immunomodulatory effects of tofacitinib on epidermal keratinocytes in in vitro and in vivo models of psoriasis. We demonstrated the selectivity of tofacitinib inhibitory action on IFN-γ and IL-22, but not on TNF-γ or IL-17 proinflammatory signaling, with suppressed expression of IFN-γ-dependent inflammatory genes, and restoration of normal proliferative and differentiative programs altered by IL-22 in psoriatic keratinocyte cultures. Tofacitinib also potently reduced the psoriasiform phenotype in the imiquimod-induced murine model of psoriasis. Finally, we found that tofacitinib mimics SOCS1 or SOCS3 activities, as it impaired the same molecular pathways in IFN-γ or IL-22-activated keratinocytes.

scholarly journals Ebosin Ameliorates Psoriasis-Like Inflammation of Mice via miR-155 Targeting tnfaip3 on IL-17 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Weiwei Guo ◽  
Fengying Xu ◽  
Zhuochen Zhuang ◽  
Zhe Liu ◽  
Jiming Xie ◽  
...  
Keyword(s):  
Signs And Symptoms ◽  
Skin Lesions ◽  
Epidermal Differentiation ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Psoriatic Skin ◽  
Direct Binding ◽  
Related Proteins

Psoriasis is a recurrent autoimmune skin disease with aberrant regulation of keratinocytes and immunocytes. There is no universally accepted single treatment available for psoriasis, and the establishment of a common treatment option to control its signs and symptoms is urgently needed. Here, we found Ebosin, a novel exopolysaccharide isolated from Streptomyces sp. 139 by our lab, not only could ameliorate inflammation in LPS-induced keratinocytes through IKK/NF-kapaB pathway, but also attenuate psoriatic skin lesions and reduce inflammatory factors expression in imiquimod (IMQ)-mediated psoriatic mice. Except for inhibiting the expression of epidermal differentiation related proteins, Ebosin significantly increased the percentage of CD4+Foxp3+CD25+ Tregs and decreased CD4+IL17A+ Th17 cells in psoriatic mice. Furthermore, we demonstrate that Ebosin significantly suppressed the IL-17 signaling pathway via A20 (encoded by tnfaip3) in vivo. As the direct binding of tnfaip3 to miR-155 has been demonstrated by luciferase reporter assay, and Ebosin has been demonstrated to inhibit miR-155 level in vitro and in vivo, our study first indicates that Ebosin reduces inflammation through the miR-155-tnfaip3-IL-17 axis and T cell differentiation in a psoriasis-like model. Thus, we conclude that Ebosin can act as a promising therapeutic candidate for the treatment of psoriasis.

Abstract 522: Specific Oxidized Phospholipids Modulate Platelet Reactivity In Vivo During Hyperlipidemia Via Cd36: A Mechanism Linking Hyperlipidemia, Oxidant Stress And A Pro-thrombotic Phenotype

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Eugene A Podrez ◽  
Tatiana V Byzova ◽  
Maria Febbraio ◽  
Robert G Salomon ◽  
Yi Ma ◽  
...  
Keyword(s):  
Platelet Reactivity ◽  
Oxidant Stress ◽  
Ldl Receptor ◽  
Biologically Active ◽  
Surface Glycoprotein ◽  
Oxidized Lipids ◽  
List Type ◽  
Platelet Surface ◽  
Clinical Associations

Enhanced platelet reactivity is critical to the pathophysiology of occlusive arterial thrombotic disease. Despite the strong clinical associations between hyperlipidemia, a major risk factor for atherosclerosis, and a pro-thrombotic phenotype, the mechanisms responsible for enhanced platelet reactivity during hyperlipidemia remain unknown. Pro-atherosclerotic lipid abnormalities such as hypercholesterolemia are associated with both enhanced oxidant stress and generation of biologically active oxidized lipids, including potential ligands for the scavenger receptor CD36, a major platelet surface glycoprotein. Using multiple murine in vivo thrombosis models we now demonstrate that hyperlipidemic atherosclerosis prone mice (apolipoprotein E-deficient or LDL receptor-deficient) form occlusive intravascular thrombi faster than wildtype mice, and that genetic deletion of CD36 protects mice from hyperlipidemia-associated enhanced platelet reactivity and accompanying pro-thrombotic phenotype. Structurally defined oxidized choline glycerophospholipid molecular species that serve as endogenous high affinity ligands for CD36 are shown to : be markedly increased in plasma of hyperlipidemic mice; be elevated in plasma of subjects with low HDL levels; and to promote platelet activation and alpha-granule release via CD36 at pathophysiological levels. These studies thus demonstrate that platelet CD36 interactions with specific endogenous oxidized lipids play a heretofore unrecognized role in the well-known clinical associations between hyperlipidemia, oxidant stress and a prothrombotic phenotype.

scholarly journals Preparation of Calcipotriol Emulsion Using Bacterial Exopolysaccharides as Emulsifier for Percutaneous Treatment of Psoriasis Vulgaris

2019 ◽  
Vol 21 (1) ◽  
pp. 77 ◽  
Author(s):  
Bo Song ◽  
Ruiteng Song ◽  
Min Cheng ◽  
Hairong Chu ◽  
Fang Yan ◽  
...  
Keyword(s):  
Psoriasis Vulgaris ◽  
Animal Experiments ◽  
Inflammatory Cells ◽  
Percutaneous Treatment ◽  
Skin Lesions ◽  
Inflammatory Factors ◽  
Psoriatic Skin ◽  
Medical Materials

An exopolysaccharides/calcipotriol (EPS/CPT) emulsion was prepared using bacterial EPS as emulsifier, sunflower oil as an oil phase and CPT as the loaded drug, and the effect of this emulsion on psoriasis vulgaris treatment was evaluated. An EPS composed of mannose (70.56%) and glucose (29.44%) was obtained from the marine mangrove bacteria Bacillus amyloliquefaciens ZWJ (Zhu Wenjing) strain. The EPS has significant emulsifying activity at the concentration of 1.5%. The prepared EPS/CPT emulsion has small and stable particle size, with a drug content of 0.00492%, and good spreading properties. The in vitro drug release results revealed that the emulsion showed a certain sustained release effect. In vitro and in vivo animal experiments show that the EPS/CPT emulsion can effectively treat psoriasis vulgaris by increasing the accumulation of CPT in psoriatic skin lesions and reducing the levels of inflammatory cells and inflammatory factors (TNF and IL6). Additionally, it has a certain effect on reducing the side effects associated with CPT. This study lays a foundation for the research of EPS in the topical application of medical materials and treatment of psoriasis.

Neutrophil Myeloperoxidase Destruction by Ultraviolet Irradiation

1988 ◽  
Vol 46 ◽  
pp. 138-139
Author(s):  
J. Hanker ◽  
B. Giammara ◽  
G. Strauss
Keyword(s):  
Uv Radiation ◽  
Myeloid Leukemia ◽  
Stratospheric Ozone ◽  
Psoriasis Patient ◽  
Whole Body ◽  
Human Neutrophils ◽  
Cupric Nitrate ◽  
The Earth ◽  
Routine Handling ◽  
Uvb Phototherapy

Only a fraction of the UV radiation emitted by the sun reaches the earth; most of the UVB (290-320nm) is eliminated by stratospheric ozone. There is increasing concern, however, that man-made chemicals are damaging this ozone layer. Although the effects of UV on DNA or as a carcinogen are widely known, preleukemia and acute myeloid leukemia (AML) have only rarely been reported in psoriasis patients treated with 8-methoxypsoralen and UV (PUVA). It was therefore of interest to study the effects of UV on the myeloperoxidase (MP) activity of human neutrophils. The peroxidase activity of enriched leukocyte preparations on coverslips was shown cytochemically with a diaminobenzidine medium and cupric nitrate intensification.Control samples (Figs. 1,4,5) of human bloods that were not specifically exposed to UV radiation or light except during routine handling were compared with samples which had been exposed in one of several different ways. One preparation (Fig. 2) was from a psoriasis patient who had received whole-body UVB phototherapy repeatedly.

Action of Lysolecithin on Blood Platelets

1963 ◽  
Vol 09 (03) ◽  
pp. 512-524 ◽  
Author(s):  
Chava Kirschmann ◽  
Sara Aloof ◽  
Andre de Vries
Keyword(s):  
Blood Platelets ◽  
Protective Action ◽  
Platelet Surface ◽  
Washed Platelet ◽  
Sufficient Concentration ◽  
Saline Medium

SummaryLysolecithin is adsorbed to washed blood platelets and, at sufficient concentration, lyses them, inhibits their clot-retracting activity and promotes their thromboplastin-generating activity. Lysolecithin adsorption to the platelet was studied by using P32-labelled lysolecithin obtained from the liver of rats injected with labelled orthophosphate. The amount of lysolecithin adsorbed to the surface of the washed platelet in saline medium is dependent on the concentration of lysolecithin in solution and reaches saturation — 5 × 10-8 jig per platelet — at a concentration of 9—10 µg per ml. Platelet lysis in saline medium begins at a lysolecithin concentration higher than 18 jig per ml. Plasma and albumin prevent adsorption of lysolecithin to the platelet and protect the platelet from damage by lysolecithin. Albumin is able to remove previously adsorbed lysolecithin from the platelet surface. The protective action of plasma explains the lack of platelet damage in blood, the plasma lecithin of which has been converted to lysolecithin by the action of Vipera palestinae venom phosphatidase, in vitro and in vivo.

LACK OF EFFECT OF CORTICOSTEROIDS ON THE IN VIVO DISAPPEARANCE OF SULFHYDRYL-INHIBITED AND ANTIBODY-COATED ERYTHROCYTES

1964 ◽  
Vol 47 (3_Suppl) ◽  
pp. S28-S36
Author(s):  
Kailash N. Agarwal
Keyword(s):  
Red Cells ◽  
List Type ◽  
Red Cell

ABSTRACT Red cells were incubated in vitro with sulfhydryl inhibitors and Rhantibody with and without prior incubation with prednisolone-hemisuccinate. These erythrocytes were labelled with Cr51 and P32 and their disappearance in vivo after autotransfusion was measured. Prior incubation with prednisolone-hemisuccinate had no effect on the rate of red cell disappearance. The disappearance of the cells was shown to take place without appreciable intravascular destruction.

STUDIES IN CONGENITAL GENERALIZED LIPODYSTROPHY

1973 ◽  
Vol 72 (3) ◽  
pp. 495-505 ◽  
Author(s):  
Oddmund Søvik ◽  
Svein Oseid
Keyword(s):  
Biological Activity ◽  
Insulin Response ◽  
Epididymal Adipose Tissue ◽  
Large Individual ◽  
Immunoreactive Insulin ◽  
List Type ◽  
Glucose Load ◽  
Congenital Generalized Lipodystrophy ◽  
The One

ABSTRACT The biological activity of plasma insulin from 4 cases of congenital generalized lipodystrophy has been studied, using rat diaphragm and epididymal adipose tissue in vivo. The results are compared with previous data on plasma immunoreactive insulin obtained in these patients. 2 of the 4 cases exhibited unusually high biological insulin activities during the fasting state as well as after an intravenous (iv) glucose load. In the fat pad assay activities as high as 10 000 μU insulin per ml were observed. During childhood the biological insulin activities were generally high, although there were large individual variations. However, in the one case studied after the age of puberty, the insulin response to a glucose load was negligible. Taken together, the biological and immunological activities observed strongly suggest the presence of pancreatic insulin in these patients. It appears that the circulating insulin has a fully biological activity. The decreasing insulin activities after cessation of growth are in agreement with the appearance of frank diabetes at this time.

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